Numerous papers over the last two decades have demonstrated that particle uptake by the gastrointestinal tract is a reality. In addition, polymeric nano- and microparticles have proved to be useful delivery systems to enhance oral bioavailability of poorly absorbed drugs or to induce mucosal immune response. However, despite the amount of data available, no set criteria are available for the design of a good particulate carrier for oral delivery of peptides or antigens. This is partly due to the publication of conflicting and confusing data. The source of discrepancy is actually multiparametric (e.g., methodology, mode of evaluation, animal species) and is still not fully understood. The purpose of this review is to discuss the advantages and the limitations of the methodologies and the models used to evaluate gastrointestinal uptake of nano- and microparticles.